Search

Abstract: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001., (© 2024 American Society of Hematology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Intracranial artery dissection is an uncommon but possible cause of ischemic stroke, and is usually diagnosed based on imaging findings such as mural hematoma and dissection flap. However, it is challenging to recognize the underlying dissection in cases of acute large vessel occlusion. In this report, we present a case of acute internal carotid artery occlusion, in which the underlying dissection of the paraclinoid segment was found during the thrombectomy procedure. Two thrombectomy procedures failed to recanalize the acute internal carotid artery occlusion without removing any clot. Angiography performed during a Trevo stent retriever deployment in the first pass showed obscure contrast defects in the stent strut with temporary flow restoration. In the next pass, the appearance of the contrast defects changed and a parallel linear contrast appeared on the outside of the vessel wall. These angiographic findings were identified as mural hematoma and dissection flap, indicating dissection of the paraclinoid as the cause of the occlusion. During antiplatelet loading and preparation of a dedicated intracranial stent, the Trevo stent retriever was left deployed again at the occlusion site to maintain the blood flow. After permanent stenting with an Enterprise stent, angiography revealed complete recanalization. The patient recovered fully after the procedure. In the present case, stent retriever deployment revealed the hallmarks of dissection on angiography, such as mural hematoma, dissection flap, and temporal morphological changes, by restoring the blood flow temporarily. Such angiographic findings can provide useful information on the occlusion characteristics and real-time feedback for optimal treatment strategy., (© 2022 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Mechanical thrombectomy is highly effective for the recovery of acute ischemic stroke with large vessel occlusion. However, refractory occlusions are still encountered despite the use of currently available devices. In this article, we present a case of refractory terminal internal carotid artery occlusion treated with the "crossing double stent retriever technique." Two thrombectomy procedures with the combined technique using a stent retriever and aspiration catheter failed to recanalize the terminal internal carotid artery occlusion that involved the dominant anterior cerebral artery. We then applied the crossing double stent retriever technique as a rescue technique. Two microcatheters were advanced across the occlusion: one to the anterior cerebral artery and the other to the middle cerebral artery. First, a Trevo NXT 4 mm stent retriever was deployed from the anterior cerebral artery. Next, an additional Trevo NXT 4 mm stent retriever was deployed from the middle cerebral artery, and full immediate restoration of flow was achieved on angiography. Intraprocedural radiological images showed that the 2 microcatheters traversed different pathways, and the 2 stent retrievers completely covered the entire vessel with apparent in-stent clot sign. Both stent retrievers were then pulled back together, and a hard clot was retrieved. Subsequent angiography revealed complete recanalization. The crossing double stent retriever technique seems an effective rescue technique for treating refractory terminal internal carotid artery occlusion, especially with the anatomical feature of branching of the dominant anterior cerebral artery. This technique can facilitate the device-clot-vessel interaction by engaging the clot via 2 different device pathways., (© 2022 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Spear-like collagen complexes, known as actinotrichia, underlie the epidermal cell layer in the tip of teleost fins and are known to contribute toward fin formation; however, their specific role remains largely unclear. In this study, we investigated of actinotrichia in the role of caudal fin formation by generating collagen9a1c (col9a1c)-knockout zebrafish. Although actinotrichia were initially produced normally and aligned correctly in the knockout fish, the number of actinotrichia decreased as the fish grew and their alignment became disordered. Simultaneously, the fin tip gradually shortened in the dorsal-ventral direction and the entire fin became oval-shaped, while the fin-rays rarely bifurcated and instead underwent fusion, suggesting that actinotrichia are essential for spreading fins dorsoventrally. Furthermore, the epithelial cells that are usually thinly spread in normal fish became spherical in the knockout fish, reducing the area covered by each cell and thus the area of the fin tip. Together, these findings suggest that the tight alignment of actinotrichia provides physical support in the dorsal-ventral direction that allows caudal fins to expand in a triangular-shape., Competing Interests: Declaration of competing interest The authors declare no competing or financial interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Several psychotropic drugs can cause cytopenia, especially after increasing dosages or initiating treatment. However, cytopenia in patients with psychiatric disorders can also be due to other conditions such as leukemia. In this report, we discuss two cases of cytopenia that occurred during the adjustment of psychotropic medications in patients with severe psychiatric illness. The initial diagnosis in each case was drug-induced cytopenia; however, later, the cause of cytopenia was found to be acute promyelocytic leukemia. When cytopenia is observed while increasing the dosage of psychotropic drugs, suspicious drugs should be discontinued, though the possibility that cytopenia could be due to other reasons should be considered. If there are no signs of recovering blood cells or if cytopenia is severe, psychiatrists should consult hematologists promptly., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Macroalgae (seaweed) has been shown to be an effective environmental indicator. We investigate the trace element chemistry of macroalgae samples from locations along the Firth of Forth and Forth Estuary in Scotland. The overall trend in elemental abundance (Os ≪ Re < Ag < U < Cd < Co < Ni < Pb < Cu < As < Zn ≪ I), and changes along the estuary (seawards: increase As, I, Cd, U, Re, Os; decrease Pb, Cu; mid-estuary peak Zn; based on certain species), are controlled by a number of factors, including: salinity, mixing and macroalgal species differences. Within the same macroalgal species, some elemental abundances (As, I, Pb, Cu, Cd and U) are affected by mixing between freshwater riverine and North Sea marine saltwater. Additional mixing of natural and anthropogenic inputs from the surrounding geology and industry are also observed, affecting Zn, Ni, Co, Re and Os. Macroalgae is also an increasingly popular food, with some species harvested in the Firth of Forth. Iodine (67-5061 ppm), lead (0.047-4.1 ppm) and cadmium (0.006-0.93 ppm) macroalgal abundances are at safe levels for human consumption (WHO limits). However, many samples exceed the American (3 ppm) and Australian (1 ppm) limits for inorganic arsenic in macroalgae, with values ranging 0-67 ppm. In most of the samples, soaking and cooking the macroalgae reduced the inorganic arsenic content to within the American and Australian limits. However, this has further implications if the macroalgae is used to cook soups (e.g., Dashi), as the leached elements become a significant component of the soup., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The embryonic fins and the tip of adult fins of teleost fish are supported by rows of straight, unmineralized fibrils called actinotrichia. The proximal ends of the actinotrichia are bundled and the mineralized bones called lepidotrichia are made along them. Since malformation in actinotrichia causes wavy fin bones, the correct configuration of actinotrichia is essential for the correct construction of the fin shape. Past studies suggested that two types of cells, basal keratinocytes, and mesenchymal cells involve in the formation of actinotrichia. However, the mechanism how these cells contribute is unknown. In this study, we elucidated the role of basal keratinocytes in actinotrichia formation. First, we developed the imaging tool that specifically visualizes the basal keratinocytes and actinotrichia. Then, we established the in vitro culture method of the basal keratinocytes and found that the keratinocytes developed fine needle-like structures in it. The TEM image of them showed the specific shadow pattern of actinotrichia, indicating that the fine needle-like structures are the newly made actinotrichia. Finally, we cultured the basal keratinocytes with mature actinotrichia and observed that the basal keratinocytes actively holded actinotrichia with their membrane, and often generated a linear array of cells holding a single actinotrichium. This behavior suggested a mechanism with which long actinotrichia are made by relatively small cells. Our results clarified the role of basal keratinocyte and provided a novel insight into understanding the mechanism of actinotrichia formation., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

A 56-year-old Japanese male with chronic active Epstein-Barr virus (EBV) infection (CAEBV) who developed systemic gamma-delta T-cell lymphoproliferative disease (LPD) is reported. Although immune cooling therapy was effective, he died of sudden and severe hypoxia and anemia soon after the initiation of cytotoxic chemotherapy that had been previously recommended. There might remain a difficulty to control fulminant adult-onset CAEBV. Additionally, we describe three types of lymphoid cells that were observed in his peripheral blood: morphologically normal lymphocytes, large blastic cells and mature ones with rough granules. Morphological observation appeared to be useful to estimate clinical manifestations. Since CAEBV is extremely rare disease in adult population, it is important to accumulate clinical data to more understand the pathogenesis or to establish treatment strategy., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Bone is a connective tissue composed of many cell types, including osteoblasts. How bones acquire their unique size and shape during development remains poorly understood. Herein we investigated the molecular and cellular mechanisms of bone morphogenesis in the zebrafish scale by using transgenic lines to enable visualization of specific types of osteoblasts. We demonstrate that the zebrafish scale contains three distinct types of osteoblasts: (i) a monolayer of central osteoblasts along the inner surface of scales; (ii) marginal osteoblasts elongated along the scale edge; and (iii) submarginal osteoblasts located between the central and marginal osteoblast populations. The size of the central osteoblasts increases progressively during development, suggesting that scale growth is mediated primarily by cell growth rather than the recruitment of new osteoblasts. In addition, the total number of central osteoblasts increases in regenerated scales and is correlated with scale size, possibly allowing for the rapid growth of regenerating scales. Moreover, osteoblast proliferation is not detected during regeneration, suggesting that the osteoblasts originate from post-mitotic precursor cells. Sonic hedgehog a (shha) is expressed in the epidermal cells that make contact with the marginal osteoblasts. Pharmacological inhibition of Hedgehog (Hh) signaling during regeneration reduces the number of marginal osteoblasts and interferes with scale growth, indicating that epidermis-derived Shh regulates scale regeneration. Finally, genetic inhibition of Wnt/planar cell polarity (PCP) signaling in the epidermis results in misorientation of scales with regard to the body axis. These results reveal a novel role for the epidermis in the regulation of bone patterning, namely the regeneration of osteoblasts and directional bone growth., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We describe the mass descrimination and validation of an offline method for purification of Li, Mg and S with an ion chromatograph coupled to an automated fraction collector for use prior to stable isotope measurements. Significant sub-fraction mass fractionation was observed for both the Li and the Mg stable isotope ratios. The lighter Li and heavier Mg isotopes were preferentially retained by the column, resulting in 7 Li/ 6 Li and 26 Mg/ 24 Mg biases up to 85.8‰ and 0.95‰, respectively. The isotopic compositions of Li, Mg, and S separated from seawater were δ 7 Li L-SVEC  = +30.9‰, δ 26 Mg DSM3  = -0.83 ± 0.10‰, and δ 34 S VCDT  = +19.4 ± 0.6‰; each chromatographic peak was completely recovered, and the results were in good agreement with the published values regardless of whether or not chemical suppressor was used. The purification method enables multi-isotope analysis of a sample using various mass spectrometry techniques, such as multiple-collector inductively coupled plasma and thermal ionization mass spectrometry., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is accompanied by an inflammatory response, which exacerbates brain injury and deteriorates functional outcome. S100A12 is expressed abundantly in granulocytes, and has been implicated to play an important role on inflammatory reactions in various disease states. We aimed to determine the association between plasma S100A12 levels and a functional outcome in patients with acute ischemic stroke., Methods: We prospectively included 171 patients with acute ischemic stroke within 24h after onset in this study. Plasma samples were collected for the measurement of S100A12 levels. Poor functional outcome was defined as a modified Rankin Scale of 2-6 at day 90 after stroke onset., Results: Of 171 patients, 74 (43.3%) had a poor functional outcome at day 90 after stroke onset. Plasma S100A12 levels on admission were significantly higher in patients with a poor functional outcome (2.1 [1.2-5.1] ng/mL, median [interquartile]) than in those with a favorable outcome (1.1 [0.5-2.0] ng/mL; p<0.001). Multivariate analysis showed that the highest quartile of plasma S100A12 levels on admission showed a significantly higher risk for a poor functional outcome (odds ratio, 4.01; 95% confidence interval, 1.09-16.10; p=0.03) than the lowest quartile., Conclusions: High plasma S100A12 levels on admission are associated with a poor functional outcome in patients with acute ischemic stroke., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background and Purpose: The findings of recent clinical trials suggest that treatment with high-dose statins reduces the risk of stroke recurrence. However, the doses approved in Japan are much lower than those in the previous studies. This study aimed to elucidate whether prescribed doses of statins reduce the risks of cerebrovascular events (CVEs: stroke recurrence or transient ischemic attack) and all-cause mortality in a cohort of Japanese patients with first-ever ischemic stroke., Methods: The 2822 eligible patients registered in the Fukuoka Stroke Registry with first-ever acute ischemic stroke from June 2007 to February 2011 were classified into statin users (n = 993) and non-users (n = 1829) at discharge, and followed up until March 2012. We assessed the cumulative risks of CVE and all-cause mortality by the Kaplan-Meier method, and calculated hazard ratios (HRs) and 95% confidential intervals (CIs) using the Cox proportional hazards model., Results: During the follow-up time (median, 2.0 years), 305 patients had CVEs and 345 died. The cumulative risks of CVE and death after 4 years were significantly lower in statin users than in non-users (13.8% versus 19.5%, P = 0.005 for CVE; 11.8% versus 21.7%, P < 0.001 for death). After adjusting for multiple confounding factors, statin treatment significantly reduced the risks of CVE (HR, 0.70; 95% CI, 0.53 to 0.92; P = 0.011) and all-cause mortality (HR, 0.67; 95% CI, 0.50 to 0.89; P = 0.006)., Conclusions: Our findings suggest that low-dose statin may reduce the risks of CVE and death in Japanese patients with acute ischemic stroke., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL), which originates from activated mature gamma-delta T cells with a cytotoxic phenotype is a rare T-cell lymphoproliferative disease. The prognosis of PCGD-TCL has been rather unfavorable due to poor response to conventional chemotherapy, and its molecular features and pathophysiology underlying disease development remain unknown. We report here a case with primarily treatment-resistant PCGD-TCL featuring highly complex cytogenetic and genetic aberrations detected by spectral karyotyping and genome-wide single nucleotide polymorphism (SNP) array. Chromosomal aberrations included several chromosomal translocations involving breakpoints at 9p21, 14q11.2, 14q32.1, or 16q23.1, suggesting the involvement of WWOX, TCL gene cluster, and BCL11B, which are crucial for tumorigenesis in T-cell lymphomas. SNP analysis also identified genome copy number gains and losses in various regions, which can potently deregulate expression of various pro- and anti-oncogenic genes involved in RAS-related protein pathways, PI3K/AKT/MTOR-related pathways, MYC-related signaling, or TP53-related signaling. Thus, this case report may shed some light on the complex molecular abnormalities involved in the development of PCGD-TCL and on information that can aid the search for druggable target molecules in this disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Many animals develop left-right (LR) asymmetry in their internal organs. The mechanisms of LR asymmetric development are evolutionarily divergent, and are poorly understood in invertebrates. Therefore, we studied the genetic pathway of LR asymmetric development in Drosophila. Drosophila has several organs that show directional and stereotypic LR asymmetry, including the embryonic gut, which is the first organ to develop LR asymmetry during Drosophila development. In this study, we found that genes encoding components of the Wnt-signaling pathway are required for LR asymmetric development of the anterior part of the embryonic midgut (AMG). frizzled 2 (fz2) and Wnt4, which encode a receptor and ligand of Wnt signaling, respectively, were required for the LR asymmetric development of the AMG. arrow (arr), an ortholog of the mammalian gene encoding low-density lipoprotein receptor-related protein 5/6, which is a co-receptor of the Wnt-signaling pathway, was also essential for LR asymmetric development of the AMG. These results are the first demonstration that Wnt signaling contributes to LR asymmetric development in invertebrates, as it does in vertebrates. The AMG consists of visceral muscle and an epithelial tube. Our genetic analyses revealed that Wnt signaling in the visceral muscle but not the epithelium of the midgut is required for the AMG to develop its normal laterality. Furthermore, fz2 and Wnt4 were expressed in the visceral muscles of the midgut. Consistent with these results, we observed that the LR asymmetric rearrangement of the visceral muscle cells, the first visible asymmetry of the developing AMG, did not occur in embryos lacking Wnt4 expression. Our results also suggest that canonical Wnt/β-catenin signaling, but not non-canonical Wnt signaling, is responsible for the LR asymmetric development of the AMG. Canonical Wnt/β-catenin signaling is reported to have important roles in LR asymmetric development in zebrafish. Thus, the contribution of canonical Wnt/β-catenin signaling to LR asymmetric development may be an evolutionarily conserved feature between vertebrates and invertebrates., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Infection with human parvovirus B19 (PVB19) induces acquired pure red cell aplasia (PRCA). Chronic hemolytic anemia is well known as an underlying condition. However, additional factors have been recognized to accompany parvoviral PRCA; however, there are only limited reports on iron-deficiency anemia (IDA) and rituximab-induced B-cell dysfunction. We report two patients with PVB19-associated PRCA confirmed by positivity of viral DNA. Although they had no chronic hemolysis, patient 1 had IDA, and patient 2 had remitted small-lymphocytic lymphoma treated with rituximab-containing chemotherapy. Absence of reticulocytes in peripheral blood and marked depletion of erythroid precursors in bone marrow were observed both. Whereas patient 1 received only symptomatic therapy because anemia was not severe, patient 2 was treated with steroids, as PRCA etiology was at first uncertain, and immunological PRCA was not excluded. Both showed rapid increase of reticulocyte counts and recovery from anemia. Although immunoglobulin is considered effective for parvoviral PRCA, notable adverse reactions have been reported. When anemic symptom is not severe, reticulocyte observation only is recommended. The effects of steroids should also be re-evaluated. Optimal treatment according to disease severity remains to be established.

Many animals exhibit stereotypical left-right (LR) asymmetry in their internal organs. The mechanisms of LR axis formation required for the subsequent LR asymmetric development are well understood, especially in some vertebrates. However, the molecular mechanisms underlying LR asymmetric morphogenesis, particularly how mechanical force is integrated into the LR asymmetric morphogenesis of organs, are poorly understood. Here, we identified zipper (zip), encoding a Drosophila non-muscle myosin II (myosin II) heavy chain, as a gene required for LR asymmetric development of the embryonic anterior midgut (AMG). Myosin II is known to directly generate mechanical force in various types of cells during morphogenesis and cell migration. We found that myosin II was involved in two events in the LR asymmetric development of the AMG. First, it introduced an LR bias to the directional position of circular visceral muscle (CVMU) cells, which externally cover the midgut epithelium. Second, it was required for the LR-biased rotation of the AMG. Our results suggest that myosin II in CVMU cells plays a crucial role in generating the force leading to LR asymmetric morphogenesis. Taken together with previous studies in vertebrates, the involvement of myosin II in LR asymmetric morphogenesis might be conserved evolutionarily., (Copyright 2010 Elsevier Inc. All rights reserved.)

We evaluated the mechanism of recognition of myeloma cells by gammadeltaT cells. The expanded gammadeltaT cells killed RPMI8226 and U266 myeloma cells in a gammadeltaT-cell dose-dependent manner. Pretreatment of myeloma cells with zoledronic acid or mevastatin showed that gammadeltaT cells kill myeloma cells by recognizing the mevalonate metabolites. The expression level of intercellular cell adhesion molecule-1 (ICAM-1) on myeloma cells correlates with the cytotoxicity by gammadeltaT cells. Pretreatment of RPMI8226 and U266 with an anti-ICAM-1 monoclonal antibody inhibited their cytolysis. Moreover, AMO-1 myeloma cells transfected with of human ICAM-1 cDNA were susceptible to gammadeltaT cells compared to parental AMO-1 cells. In conclusion, gammadeltaT cells recognize the mevalonate metabolites and ICAM-1 on myeloma cells.

Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

Metallothionein (MT) is a low-molecular-weight cysteine-rich protein which has a high affinity for metals. The synthesis of MT is induced by heavy metals such as cadmium and zinc. However, little is known about the induction of MT by tetravalent or pentavalent metals. We investigated the induction of MT synthesis by a pentavalent vanadium compound in mice. Hepatic MT concentrations were increased by subcutaneous injection of ammonium metavanadate (AMV) dose-dependently, and to the similar levels as those induced by zinc chloride. However, accumulation of vanadium in the liver was very low, while high concentrations of vanadium were detected in the kidney. High performance liquid chromatography/inductively coupled argon plasma-mass spectrometry (HPLC/ICP-MS) chromatogram of the liver cytosol of AMV-treated mice revealed that the major metal bound to MT was not vanadium, but zinc. The chromatogram of the liver cytosol of MT null mice demonstrated the existence of a low-molecular-weight vanadium-binding protein that is different from MT. A time-course study showed that concentrations of serum interleukin-6 (IL-6) and serum amyloid A (SAA), an acute-phase protein, increased after the AMV injection. To confirm the involvement of IL-6 in MT induction by AMV administration, IL-6 null and wild-type mice were injected with AMV. In IL-6 null mice, hepatic MT induction by AMV administration decreased significantly to about a half of wild-type mice. These data suggest that both IL-6-dependent and -independent mechanisms are involved in MT induction by vanadium compounds in mice.

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.

Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CML), but remissions induced in advanced-phase CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate.

We describe herein a case of nephrotic syndrome (NS) following allogeneic bone marrow transplantation (allo-BMT) for natural killer cell leukemia/lymphoma. Histologic studies defined the diagnosis as crescentic glomerulonephritis with massive immunoglobulin A (IgA) deposition, which has never been reported in NS cases following allo-BMT. Most of the massive infiltrated cells in the interstice were CD3(+)CD4(-)CD8(+) T cells derived from the donor. We observed mesangial deposition of Haemophilus parainfluenza outer membrane (OMHP) antigen and decreased glycosylation of the IgA1 hinge in the recipient's samples is consistent with the recently reported pathogenesis of IgA nephropathy. Further, the titer of IgA antibody against the donor serum was as high as other IgA nephropathy cases. These findings suggest that NS and crescentic glomerulonephritis in this case occurred as one of the forms of chronic graft-versus-host disease (GVHD), and that IgA deposition was associated with H parainfluenza and decreased glycosylation of the IgA1 hinge.

Cerebral cortical cells from fetal rats (14 days) were cultured in vitro (7-104 days). Localization of synaptophysin was examined immunocytochemically using a monoclonal antibody (SY-38) against synaptophysin. Synaptophysin-immunoreactive (SP-IR) spots were distributed on the surface of the cells. Electron-microscopic observation showed that the SP-IR staining was localized at presynaptic terminals, indicating that the SP-IR spots observed will, fluorescence microscopy represent presynaptic terminals. The time-course of the distribution of SP-IR spots was examined. SP-IR spots could not be observed in cells at 7 days in vitro (DIV). At 14 DIV, SP-IR spots could be first observed on the surface of cell bodies and neurites. Thereafter, the density of SP-IR spots on the cell bodies and neurites increased with DIV. At 42 and 104 DIV, SP-IR spots were almost continued, surrounding the neurites and cell bodies of the cultured cells. These immunocytochemical studies suggest that the dissociated 14-day fetal cerebral cortical neurons make synapses by at least 14 DIV and that the density of synapses increases with time.

Cytoplasmic and nuclear accumulation of glycogen granules in the kidney cells of 72 male WBN/Kob rats with a long-term diabetic condition was studied histologically and by electron microscopy. The incidence and degree of the accumulation showed good correlation with the blood glucose concentration. In the kidneys, there was evidence of two types of lesion, cytoplasmic glycogen accumulation in the distal convoluted tubules and nuclear accumulation in the ascending thick segment of Henle's loops. Electron microscopically, the cytoplasmic glycogen accumulation was often associated with an increased number of lysosomal bodies containing lamellar bodies. Glycogen bodies, the halo of which was thought to be identical with that of nuclear bodies, were frequently observed in the nuclei containing the glycogen granules. These morphological and topographical differences between the two types of lesion were considered suggestive of different pathogenetic mechanisms for glycogen accumulation in the kidney cells.